Along with the dynamics of population aging, an increase in the number of patients in a state of lowered cognitive function, that is, patients having a demential disease, poses a social problem. The demential disease is defined as “a state in which memory function and other cognitive functions have been deteriorated to the extent that the everyday life is interfered with, by the organic changes occurring in the brain as a result of cerebrovascular diseases, Alzheimer's disease and other factors.”
Dementia is largely classified into vascular dementia and degenerative dementia based on the cause, but all of them result in falling off of nerve cells. Under the current situation where no effective methods for recovery therefrom are known, the inhibition of disease progression will be the primary goal.
Known as one type of degenerative dementia, Alzheimer type dementia is estimated to affect approximately 18 million patients over the world, the number being anticipated to further increase in the future, and the development of a method for prevention or a method for treatment is expected. As pathological features of Alzheimer type dementia, cerebral tissue atrophy and emergence of senile plaque in the cerebral cortex may be mentioned, and it is found that senile plaque is associated with deposition of β-amyloid.
As a method for treating Alzheimer type dementia, there is known development of a new drug based on the cholinergic hypothesis (Non-Patent Document 1), or a new drug based on the amyloid cascade hypothesis (Non-Patent Document 2).
Among them, the cholinergic hypothesis is based on the fact that the acetylcholine synthetase activity is specifically reduced in the cerebral cortex of Alzheimer type dementia patients, and the hypothesis is associated with a perspective that supplementation of the amount of acetylcholine by any means will lead to the treatment. As a therapeutic agent based on this hypothesis, donepezil hydrochloride which has an inhibitory action against acetylcholinesterase, an acetylcholine degrading enzyme, has been created, and is producing certain effects. However, since the drug based on the cholinergic hypothesis is targeted to the reinforcement of neural circuitry, there are limits on the effectiveness of the drug in regard to the fact that nerve cells keep on falling off, along with the progress of the disease condition.
On the other hand, the amyloid cascade hypothesis is associated with a perspective that aggregation and deposition of β-amyloid bring about changes in neurofibrils, eventually causing nerve cell death, and prevention of the β-amyloid deposition will lead to the treatment. As a therapeutic drug based on this hypothesis, development of an inhibitor against γ-secretase, a vaccine and the like is being anticipated, but due to the problems of adverse side effects, marketing thereof has not yet been achieved (Non-Patent Document 3).
As another approach, based on the report of epidemiological data showing that patients taking a HMG-CoA reductase inhibitor (hereinafter, may also be referred to as a statin), which is a therapeutic agent for hyperlipidemia, exhibit a low morbidity rate for Alzheimer type dementia (Non-Patent Document 4), or the finding that statins decrease the production of β-amyloid, a possibility of utilizing statins as a therapeutic agent for Alzheimer type dementia has been reported (Patent Documents 1 to 8). It has been also reported that statins have an inhibitory action against the formation of active γ-secretase complexes (Patent Document 9).
The following reports are found in regard to the action of the above-mentioned drugs on nerve cell death. Specifically, donepezil hydrochloride is known to have a protective action against the neurotoxicity of β-amyloid or glutamic acid (Non-Patent Documents 5 and 6), or a nerve cell protective action in an ischemic model (Non-Patent Document 7). However, all of these represent results obtained in vitro, and since the concentration exhibiting a nerve protective action requires a higher dose than the concentration exhibiting an acetylcholinesterase inhibitory action, it is not certain as to whether the nerve cell protective action is manifested in patients administered with the drug, or not.
Furthermore, in the case of statins, a statin suppresses an increase in the size of cerebral infarction in an animal model of transient cerebral ischemia is reported (Non-Patent Document 8), and a statin exhibits a nerve cell protective action through a suppressive action on superoxide dismutase reduction is known (Non-Patent Document 9).
Also known is a report that an acetylcholinesterase inhibitor such as donepezil hydrochloride and a statin are combined and applied to Alzheimer type dementia (Patent Document 10). However, this document does not present any specific data, and it is not certain of specifically what combination of drugs would be optimal. In addition to that, there are known clinical results obtained by using galantamine which is an acetylcholinesterase inhibitor, and a statin in combination, and it is pointed out that in the case of combined treatment, the risk of adverse side effects is increased in comparison to the case of single drug treatment (Patent Document 11). However, it is not reported that donepezil hydrochloride has a nerve protective action against transient cerebral ischemia.
As discussed so far, a drug satisfactorily having an effective nerve cell death inhibitory action against demential diseases including Alzheimer type dementia, does not yet exist, and it is desired to provide such a drug. Furthermore, a drug having an effective nerve cell death inhibitory action is also useful as a prophylactic agent against the recurrence of cerebral infarction, and therefore a prophylactic and/or therapeutic agent for cerebral infarction, in addition to demential diseases.    [Patent Document 1] WO 02/062824    [Patent Document 2] WO 01/096311    [Patent Document 3] WO 01/032161    [Patent Document 4] WO 00/028981    [Patent Document 5] WO 99/048488    [Patent Document 6] U.S. Pat. No. 6,472,421    [Patent Document 7] U.S. Pat. No. 6,440,387    [Patent Document 8] U.S. Pat. No. 6,080,778    [Patent Document 9] WO 2005/063294    [Patent Document 10] WO 2005/099823    [Patent Document 11] WO 03/082298    [Non-Patent Document 1] Science, 219:1184-1190, 1983    [Non-Patent Document 2] Science, 256:184-185, 1992    [Non-Patent Document 3] Proc. Natl. Acad. Sci. USA, 98:9312-9317, 2001    [Non-Patent Document 4] Arch. Neurol., 57:1439-1443, 2000    [Non-Patent Document 5] Neuroreport, 9:1519-1522, 1998    [Non-Patent Document 6] J. Pharmacol. Exp. Ther., 306:772-777, 2003    [Non-Patent Document 7] Eur. J. Pharmacol., 472:57-63, 2003    [Non-Patent Document 8] Brain Research, 1037:52-58, 2005    [Non-Patent Document 9] Therapeutic Research, 26:1277-1286, 2005